Low Cross-Talk Fast Sample Delivery System Based Upon Acoustic Droplet Ejection

ABSTRACT

An ion source for a mass spectrometer is disclosed comprising an ultrasonic transducer which focuses ultrasonic energy onto a surface of a sample fluid without directly contacting the sample fluid.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims priority from and the benefit of United KingdomPatent Application No. 1120141.5 filed on 22 Nov. 2011. The entirecontents of this application is incorporated herein by reference.

BACKGROUND TO THE PRESENT INVENTION

It is an increasingly common requirement of mass spectrometers to beable to rapidly process many samples. The sample may be a knownsubstance and may have a known concentration. Alternatively, the samplemay be unknown.

Injectors used in LC systems are known to be prone to samplecontamination or cross-talk and a considerable amount of effort isexpended during the design of these systems to seek to reduce thecross-talk or sample carry over that occurs in needle and sampletransfer lines. Several “blank” or solvent injections are often requiredto be run in between injections to ensure that such systems are free ofcarry-over. This results in a reduction in the duty cycle of the systemand less samples being analysed than could otherwise be possiblyachievable.

It is desired to provide an improved ion source and method of ionising asample.

SUMMARY OF THE PRESENT INVENTION

According to the present invention there is provided an ion source for amass spectrometer comprising:

an ultrasonic transducer arranged and adapted to focus ultrasonic energyonto a surface of a sample fluid without the ultrasonic transducerdirectly contacting the sample fluid.

It is known to place fluid in direct contact with an inexpensiveultrasonic transducer which will result in an uncontrolled mist ofdroplets being formed. For example, it is known to use such devices tocreate a mist for air humidifiers. According to the present invention amore sophisticated and expensive ultrasonic transducer which is capableof focusing ultrasonic energy onto a surface of a fluid sample isutilised. It is not possible with a standard inexpensive transducer asused, for example, in an air humidifier to focus the ultrasonic energy.Importantly, the ultrasonic transducer according to the presentinvention does not directly contact the sample fluid. The sample fluidmay, for example, be contained within a sample well of a microtitreplate and the ultrasonic transducer may be placed below the microtitreplate. According to the present invention ultrasonic energy is focusedon to a surface of a sample fluid and this preferably causes one or morecarefully controlled droplets to be ejected from the fluid sample in aprecisely controlled manner. The droplets may, for example, have avolume of 2.5 nL and are preferably ejected individually andsequentially. The droplets are then preferably ionised by, for example,charged droplets emerging from an Electrospray ion source.

The present invention is particularly advantageous in that the means ofejecting droplets (i.e. the ultrasonic transducer) does not directlycontact the fluid sample in contrast to e.g. LC injectors. As a result,the present invention solves the problem of cross talk which is commonproblem with e.g. injectors used in LC systems and other types of ionsources.

The present invention therefore enables droplets to be precisely andcarefully ejected from e.g. different sample wells of a microtitre platein a carefully controlled and rapid manner without the ion sourcesuffering from the problem of cross contamination.

It is apparent, therefore, that the present invention is particularlyadvantageous.

According to the preferred embodiment the ultrasonic transducer isarranged and adapted to eject one or more droplets from the sample fluidin a substantially controlled manner.

The ultrasonic transducer is preferably arranged and adapted to ejectmultiple sequential individual droplets from the sample fluid in asubstantially controlled manner.

The ultrasonic transducer is preferably arranged and adapted to ejectone or more droplets from the sample fluid without forming anuncontrolled mist of droplets.

The ultrasonic transducer is preferably arranged and adapted to ejectone or more droplets from the sample fluid wherein each droplet has avolume in the range: (i) <1 nL; (ii) 1-2 nL; (iii) 2-3 nL; (iv) 3-4 nL;(v) 4-5 nL; (vi) 5-6 nL; (vii) 6-7 nL; (viii) 7-8 nL; (ix) 8-9 nL; (x)9-10 nL; (xi) 10-15 nL; (xii) 15-20 nL; (xiii) 20-25 nL; (xiv) 25-30 nL;and (xv) >30 nL.

The ultrasonic transducer is preferably arranged and adapted to ejectone droplet from the sample fluid every 1-100 μs, 100-200 μs, 200-300μs, 300-400 μs, 400-500 μs, 500-600 μs, 600-700 μs, 700-800 μs, 800-900μs, 900-1000 μs, 1-10 ms, 10-20 ms, 20-30 ms, 30-40 ms, 40-50 ms, 50-60ms, 60-70 ms, 70-80 ms, 80-90 ms, 90-100 ms, 100-200 ms, 200-300 ms,300-400 ms, 400-500 ms, 500-600 ms, 600-700 ms, 700-800 ms, 800-900 ms,900-1000 ms or >1 s.

According to an embodiment the one or more droplets predominantlycomprise ionised droplets. The one or more droplets are preferablyionised by charge segregation.

The sample fluid preferably comprises a polar sample, an ionic sample ora non-polar sample.

According to another embodiment the one or more droplets may comprise amajority of un-ionised droplets.

The ion source preferably further comprises an ionisation device.According to an embodiment the ionisation device comprises anAtmospheric Pressure Ionisation (“API”) ionisation device. For example,according to an embodiment the Atmospheric Pressure Ionisationionisation device may comprise an Electrospray ion source, anAtmospheric Pressure Chemical Ionisation (“APCI”) ion source, anImpactor ion source wherein a sample is ionised upon impacting a target,a Laser ion source, an ultra-violet (“UV”) photoionisation device or aninfra-red (“IR”) photoionisation device.

The ionisation device is preferably arranged and adapted to ionise theone or more droplets ejected from the sample fluid by the ultrasonictransducer.

The ionisation device is preferably arranged and adapted to act as asource of secondary ionisation for droplets ejected from the samplefluid by the ultrasonic transducer.

According to an embodiment the ultrasonic transducer is arranged andadapted to eject one or more droplets from the sample fluid into astream of droplets or ions emitted by the ionisation device.

The ion source preferably further comprises a device arranged andadapted to position a sample well of a microtitre or multi-well sampleplate adjacent the ultrasonic transducer.

In a mode of operation the ultrasonic transducer remains essentiallystatic and the microtitre or multi-well sample plate is translatedrelative to the ultrasonic transducer.

In another embodiment the ion source comprises a device arranged andadapted to position the ultrasonic transducer adjacent a sample well ofa microtitre or multi-well sample plate.

According to another embodiment in a mode of operation the microtitre ormulti-well sample plate remains essentially static and the ultrasonictransducer is translated relative to the microtitre or multi-well sampleplate.

The sample fluid is preferably contained, in use, within the sample wellof the microtitre or multi-well sample plate.

The ultrasonic transducer is preferably arranged to make fluid contactwith the microtitre or multi-well sample plate.

In a mode of operation one or more droplets are preferably sequentiallyejected from different sample wells of the microtitre or multi-wellsample plate.

The ultrasonic transducer is preferably arranged and adapted to detectand/or measure reflected ultrasonic energy (in contrast to basicinexpensive ultrasonic transducers as used, for example, in airhumidifiers which have no capability to detect or measure reflectedultrasonic energy).

The ion source preferably further comprises a control system which isarranged and adapted to determine one or more first properties of thesample fluid.

According to an embodiment the control system is arranged and adapted todetermine the surface height and/or surface position and/or density ofthe sample fluid.

The control system is preferably arranged and adapted to determine oneor more first properties of the sample fluid using sonar.

The control system is preferably arranged and adapted to determine oneor more first properties of the sample fluid by determining the time offlight and intensity or energy of a reflected sonar pulse.

According to an embodiment the sonar pulse has an energy in therange<100 mW, 100-200 mW, 200-300 mW, 300-400 mW or 400-500 mW and/orhas a relative low energy so as not to cause ejection of droplets fromthe sample fluid.

The sonar pulse preferably reflects, in use, from a surface of thesample fluid.

The control system is preferably arranged and adapted to control thefocusing of the ultrasonic energy onto the surface of the sample fluidbased upon the determined one or more first properties of the samplefluid.

The ultrasonic transducer is preferably arranged to emit ultrasonicwaves having a frequency in the range: (i) 20-30 kHz; (ii) 30-40 kHz;(iii) 40-50 kHz; (iv) 50-60 kHz; (v) 60-70 kHz; (vi) 70-80 kHz; (v)i)80-90 kHz; (viii) 90-100 kHz; and (ix) >100 kHz.

According to another aspect of the present invention there is provided amass spectrometer comprising an ion source as described above.

The mass spectrometer preferably comprises an ion inlet. The ion inletpreferably leads from a substantially atmospheric pressure region to asubstantially sub-atmospheric pressure region.

The ultrasonic transducer is preferably arranged and adapted to ejectone or more droplets adjacent the ion inlet so that resulting analytemolecules and/or ions enter the mass spectrometer via the ion inlet.

The mass spectrometer preferably further comprises a gas phase ionmobility spectrometer or separator, wherein the ion mobilityspectrometer or separator is arranged and adapted to separate analyteions temporally according to their ion mobility.

According to another aspect of the present invention there is provided amethod of ionising a sample comprising:

focusing ultrasonic energy onto a surface of a sample fluid withoutdirectly contacting the sample fluid.

The method preferably further comprises ionising droplets ejected fromthe sample fluid using an Atmospheric Pressure Ionisation (“API”)device.

According to another aspect of the present invention there is provided amethod of mass spectrometry comprising a method of ionising a sample asdescribed above.

According to another aspect of the present invention there is providedan ion source for a mass spectrometer comprising:

an ultrasonic transducer arranged and adapted to focus ultrasonic energyonto a surface of a sample fluid contained, in use, within a sample wellwithout the ultrasonic transducer directly contacting the sample fluidso as to eject one or more droplets from the sample fluid in acontrolled manner without forming an uncontrolled mist of droplets; and

an ionisation device arranged and adapted to ionise the one or moredroplets.

According to another aspect of the present invention there is provided amethod of ionising a sample comprising:

providing an ultrasonic transducer and focusing ultrasonic energy onto asurface of a sample fluid contained within a sample well without theultrasonic transducer directly contacting the sample fluid no as toeject one or more droplets from the sample fluid in a controlled mannerwithout forming an uncontrolled mist of droplets; and

ionising the one or more droplets.

According to an embodiment the mass spectrometer may further comprise:

(a) an ion source selected from the group consisting of: (i) anElectrospray ionisation (“ESI”) ion source; (ii) an Atmospheric PressurePhoto Ionisation (“APPI”) ion source; (iii) an Atmospheric PressureChemical Ionisation (“APCI”) ion source; (iv) a Matrix Assisted LaserDesorption Ionisation (“MALDI”) ion source; (v) a Laser DesorptionIonisation (“LDI”) ion source; (vi) an Atmospheric Pressure Ionisation(“API”) ion source; (vii) a Desorption Ionisation on Silicon (“DIOS”)ion source; (viii) an Electron Impact (“EI”) ion source; (ix) a ChemicalIonisation (“CI”) ion source; (x) a Field Ionisation (“FI”) ion source;(xi) a Field Desorption (“FD”) ion source; (xii) an Inductively CoupledPlasma (“ICP”) ion source; (xiii) a Fast Atom Bombardment (“FAB”) ionsource; (xiv) a Liquid Secondary Ion Mass Spectrometry (“LSIMS”) ionsource; (xv) a Desorption Electrospray Ionisation (“DESI”) ion source;(xvi) a Nickel-63 radioactive ion source; (xvii) an Atmospheric PressureMatrix Assisted Laser Desorption Ionisation ion source; (xviii) aThermospray ion source; (xix) an Atmospheric Sampling Glow DischargeIonisation (“ASGDI”) ion source; (xx) a Glow Discharge (“GD”) ionsource; and (xxi) an Impactor ion source; and/or

(b) one or more continuous or pulsed ion sources; and/or

(c) one or more ion guides; and/or

(d) one or more ion mobility separation devices and/or one or more FieldAsymmetric Ion Mobility Spectrometer devices; and/or

(e) one or more ion traps or one or more ion trapping regions; and/or

(f) one or more collision, fragmentation or reaction cells selected fromthe group consisting of: (i) a Collisional Induced Dissociation (“CID”)fragmentation device; (ii) a Surface Induced Dissociation (“SID”)fragmentation device; (iii) an Electron Transfer Dissociation (“ETD”)fragmentation device; (iv) an Electron Capture Dissociation (“ECD”)fragmentation device; (v) an Electron Collision or Impact Dissociationfragmentation device; (vi) a Photo Induced Dissociation (“RID”)fragmentation device; (vii) a Laser Induced Dissociation fragmentationdevice; (viii) an infrared radiation induced dissociation device; (ix)an ultraviolet radiation induced dissociation device; (x) anozzle-skimmer interface fragmentation device; (xi) an in-sourcefragmentation device; (xii) an in-source Collision Induced Dissociationfragmentation device; (xiii) a thermal or temperature sourcefragmentation device; (xiv) an electric field induced fragmentationdevice; (xv) a magnetic field induced fragmentation device; (xvi) anenzyme digestion or enzyme degradation fragmentation device; (xvii) anion-ion reaction fragmentation device; (xviii) an ion-molecule reactionfragmentation device; (xix) an ion-atom reaction fragmentation device;(xx) an ion-metastable ion reaction fragmentation device; (xxi) anion-metastable molecule reaction fragmentation device; (xxii) anion-metastable atom reaction fragmentation device; (xxiii) an ion-ionreaction device for reacting ions to form adduct or product ions; (xxiv)an ion-molecule reaction device for reacting ions to form adduct orproduct ions; (xxv) an ion-atom reaction device for reacting ions toform adduct or product ions; (xxvi) an ion-metastable ion reactiondevice for reacting ions to form adduct or product ions; (xxvii) anion-metastable molecule reaction device for reacting ions to form adductor product ions; (xxviii) an ion-metastable atom reaction device forreacting ions to form adduct or product ions; and (xxix) an ElectronIonisation Dissociation (“EID”) fragmentation device; and/or

(g) a mass analyser selected from the group consisting of: (i) aquadrupole mass analyser; (ii) a 2D or linear quadrupole mass analyser;(iii) a Paul or 3D quadrupole mass analyser; (iv) a Penning trap massanalyser; (v) an ion trap mass analyser; (vi) a magnetic sector massanalyser; (vii) Ion Cyclotron Resonance (“ICR”) mass analyser; (viii) aFourier Transform Ion Cyclotron Resonance (“FTICR”) mass analyser; (ix)an electrostatic or orbitrap mass analyser; (x) a Fourier Transformelectrostatic or orbitrap mass analyser; (xi) a Fourier Transform massanalyser; (xii) a Time of Flight mass analyser; (xiii) an orthogonalacceleration Time of Flight mass analyser; and (xiv) a linearacceleration Time of Flight mass analyser; and/or

(h) one or more energy analysers or electrostatic energy analysers;and/or

(i) one or more ion detectors; and/or

(j) one or more mass filters selected from the group consisting of: (i)a quadrupole mass filter; (ii) a 2D or linear quadrupole ion trap; (iii)a Paul or 3D quadrupole ion trap; (iv) a Penning ion trap; (v) an iontrap; (vi) a magnetic sector mass filter; (vii) a Time of Flight massfilter; and (viii) a Wein filter; and/or

(k) a device or ion gate for pulsing ions; and/or

(l) a device for converting a substantially continuous ion beam into apulsed ion beam.

The mass spectrometer may further comprise either:

(i) a C-trap and an orbitrap (RTM) mass analyser comprising an outerbarrel-like electrode and a coaxial inner spindle-like electrode,wherein in a first mode of operation ions are transmitted to the C-trapand are then injected into the orbitrap (RTM) mass analyser and whereinin a second mode of operation ions are transmitted to the C-trap andthen to a collision cell or Electron Transfer Dissociation devicewherein at least some ions are fragmented into fragment ions, andwherein the fragment ions are then transmitted to the C-trap beforebeing injected into the orbitrap (RTM) mass analyser; and/or

(ii) a stacked ring ion guide comprising a plurality of electrodes eachhaving an aperture through which ions are transmitted in use and whereinthe spacing of the electrodes increases along the length of the ionpath, and wherein the apertures in the electrodes in an upstream sectionof the ion guide have a first diameter and wherein the apertures in theelectrodes in a downstream section of the ion guide have a seconddiameter which is smaller than the first diameter, and wherein oppositephases of an AC or RF voltage are applied, in use, to successiveelectrodes.

According to an embodiment the mass spectrometer further comprises adevice arranged and adapted to supply an AC or RF voltage to theelectrodes. The AC or RF voltage preferably has an amplitude selectedfrom the group consisting of: (i) <50 V peak to peak; (ii) 50-100 V peakto peak; (iii) 100-150 V peak to peak; (iv) 150-200 V peak to peak; (v)200-250 V peak to peak; (vi) 250-300 V peak to peak; (vii) 300-350 Vpeak to peak; (viii) 350-400 V peak to peak; (ix) 400-450 V peak topeak; (x) 450-500 V peak to peak; and (xi) >500 V peak to peak.

The AC or RF voltage preferably has a frequency selected from the groupconsisting of: (i) <100 kHz; (ii) 100-200 kHz; (iii) 200-300 kHz; (iv)300-400 kHz; (v) 400-500 kHz; (vi) 0.5-1.0 MHz; (vii) 1.0-1.5 MHz;(viii) 1.5-2.0 MHz; (ix) 2.0-2.5 MHz; (x) 2.5-3.0 MHz; (xi) 3.0-3.5 MHz;(xii) 3.5-4.0 MHz; (xiii) 4.0-4.5 MHz; (xiv) 4.5-5.0 MHz; (xv) 5.0-5.5MHz; (xvi) 5.5-6.0 MHz; (xvii) 6.0-6.5 MHz; (xviii) 6.5-7.0 MHz; (xix)7.0-7.5 MHz; (xx) 7.5-8.0 MHz; (xxi) 8.0-8.5 MHz; (xxii) 8.5-9.0 MHz;(xxiii) 9.0-9.5 MHz; (xxiv) 9.5-10.0 MHz; and (xxv) >10.0 MHz.

BRIEF DESCRIPTION OF THE DRAWINGS

Various embodiments of the present invention will now be described, byway of example only, and with reference to the accompanying drawing inwhich:

FIG. 1 shows a preferred embodiment of the present invention wherein anultrasonic transducer sequentially emits droplets from a well of amicrotitre plate and wherein the droplets are ionised by ioniseddroplets emitted from an Electrospray ion source.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENT

A preferred embodiment of the present invention will now be describedwith reference to FIG. 1.

FIG. 1 shows a preferred embodiment of the present invention wherein anultrasonic transducer is arranged so as to sequentially emit singledroplets from a well of a microtitre plate and wherein the droplets aresubsequently ionised by ionised droplets emitted from an Electrosprayion source.

According to the preferred embodiment an acoustic droplet ejectiontechnique is used as a liquid transfer process that allows bothvolumetric and positional control of liquid droplets without therequirement for needles or nozzles. The technique focuses ultrasonicenergy onto a fluid surface causing a small droplet to be ejected.Droplets with a volume as low as 1 pL and as high as 10 mL may beejected. The system can be configured to eject droplets in sequenceallowing larger volumes of liquid to be ejected from the surface.Advantageously, the method of ejecting droplets which are preferablyionised by an Electrospray or other atmospheric pressure ion source doesnot require disposable tips or nozzles. A yet further advantage is thatthere is no requirement to wash and clean the transfer mechanism therebysaving both time and cost.

It will be apparent to a person skilled in the art that the approach ofdispensing individual droplets in a controlled manner whilst eliminatingthe chance of cross-contamination has particular utility with biologicalsamples dispensed in multiple different wells of e.g. a microtitreplate.

According to an embodiment of the present invention ultrasonic energy orsound waves are transmitted by an ultrasonic transducer through the baseof a sample well and through a fluid located within the sample well. Thepressure of the ultrasonic energy or wave is preferably focussed at thesurface of the sample fluid and causes a droplet of fluid to be ejectedfrom the sample fluid in a carefully controlled manner.

The ultrasonic transducer is preferably kept in a fixed relationshipwith an ion inlet into a vacuum chamber of a mass spectrometer and amicrotitre plate is preferably translated so as to bring differentsample wells in the microtitre plate into contact with the ultrasonictransducer. The ultrasonic transducer preferably makes fluid contactwith the underside of the microtitre plate in order to ensure acontrolled transmission of sound energy into and through the samplewell.

According to a preferred embodiment the non-contact and accuratevolumetric droplet delivery system is preferably coupled with asecondary ionisation mechanism (e.g. Extractive Electrospray) and a massspectrometer to produce a fast, low cross-contamination sample deliverysystem.

According to an embodiment droplets may be ejected by the ultrasonictransducer into an ultrasonic trap. The droplets may then be trappedand/or levitated and a field may be applied in order to ionise thedroplets by a process known as Field Induced Droplet Ionization(“FIDI”). This allows direct Electrospray from the droplets without theneed for additional solvent.

In order to locate the surface of the sample fluid a low energy sonarpulse is preferably directed into the sample fluid in order to determinethe density and the depth of the sample fluid. A portion of the sonarpulse is reflected back from each interface encountered by the sonarpulse. For example, a first echo is reflected from the bottom surface ofthe microtitre plate and another second echo is received from the insidebottom of a well of the microtitre plate. A further third echo isreceived from the surface of the liquid which forms a liquid:airinterface. The ratio of the energy of the first and second echoes isused to determine the acoustic impedance of the fluid which enables thespeed of sound in the liquid to be determined. This in turn enables thedepth of the sample fluid to be determined by measuring the time takenfor sound to be reflected from the liquid:air interface. The ultrasonictransducer can then be arranged so as to focus ultrasonic or acousticenergy onto a surface of the sample fluid in an optimal manner.

Although the present invention has been described with reference topreferred embodiments, it will be understood by those skilled in the artthat various changes in form and detail may be made without departingfrom the scope of the invention as set forth in the accompanying claims.

1. An ion source for a mass spectrometer comprising: an ultrasonictransducer arranged and adapted to focus ultrasonic energy onto asurface of a sample fluid without said ultrasonic transducer directlycontacting said sample fluid.
 2. An ion source as claimed in claim 1,wherein said ultrasonic transducer is arranged and adapted to eject oneor more droplets from said sample fluid in a substantially controlledmanner.
 3. An ion source as claimed in claim 1 or 2, wherein saidultrasonic transducer is arranged and adapted to eject multiplesequential individual droplets from said sample fluid in a substantiallycontrolled manner.
 4. An ion source as claimed in any of claim 1, 2 or3, wherein said ultrasonic transducer is arranged and adapted to ejectone or more droplets from said sample fluid without forming anuncontrolled mist of droplets.
 5. An ion source as claimed in anypreceding claim, wherein said ultrasonic transducer is arranged andadapted to eject one or more droplets from said sample fluid whereineach droplet has a volume in the range: (i) <1 nL; (ii) 1-2 nL; (iii)2-3 nL; (iv) 3-4 nL; (v) 4-5nL; (vi) 5-6 nL; (vii) 6-7 nL; (viii) 7-8nL; (ix) 8-9 nL; (x) 9-10 nL; (xi) 10-15 nL; (xii) 15-20 nL; (xiii)20-25 nL; (xiv) 25-30 nL; and (xv) >30 nL.
 6. An ion source as claimedin any preceding claim, wherein said ultrasonic transducer is arrangedand adapted to eject one droplet from said sample fluid every 1-100 μs,100-200 μs, 200-300 μs, 300-400 μs, 400-500 μs, 500-600 μs, 600-700 μs,700-800 μs, 800-900 μs, 900-1000 μs, 1-10 ms, 10-20 ms, 20-30 ms, 30-40ms, 40-50 ms, 50-60 ms, 60-70 ms, 70-80 ms, 80-90 ms, 90-100 ms, 100-200ms, 200-300 ms, 300-400 ms, 400-500 ms, 500-600 ms, 600-700 ms, 700-800ms, 800-900 ms, 900-1000 ms or >1 s.
 7. An ion source as claimed in anyof claims 2-6, wherein said one or more droplets predominantly compriseionised droplets.
 8. An ion source as claimed in claim 7, wherein saidone or more droplets are ionised by charge segregation.
 9. An ion sourceas claimed in any of claims 2-6, wherein said one or more dropletscomprise a majority of un-ionised droplets.
 10. An ion source as claimedin any preceding claim, wherein said sample fluid comprises a polarsample, an ionic sample or a non-polar sample.
 11. An ion source asclaimed in any preceding claim, further comprising an ionisation device.12. An ion source as claimed in claim 11, wherein said ionisation devicecomprises an Atmospheric Pressure Ionisation (“API”) ionisation device.13. An ion source as claimed in claim 12, wherein said AtmosphericPressure Ionisation ionisation device comprises an Electrospray ionsource, an Atmospheric Pressure Chemical Ionisation (“APCI”) ion source,an Impactor ion source wherein a sample is ionised upon impacting atarget, a Laser ion source, an ultra-violet (“UV”) photoionisationdevice or an infra-red (“IR”) photoionisation device.
 14. An ion sourceas claimed in claim 11, 12 or 13, wherein said ionisation device isarranged and adapted to ionise said one or more droplets ejected fromsaid sample fluid by said ultrasonic transducer.
 15. An ion source asclaimed in any of claims 11-14, wherein said ionisation device isarranged and adapted to act as a source of secondary ionisation fordroplets ejected from said sample fluid by said ultrasonic transducer.16. An ion source as claimed in any of claims 11-15, wherein saidultrasonic transducer is arranged and adapted to eject one or moredroplets from said sample fluid into a stream of ions emitted by saidionisation device.
 17. An ion source as claimed in any preceding claim,further comprising a device arranged and adapted to position a samplewell of a microtitre or multi-well sample plate adjacent said ultrasonictransducer.
 18. An ion source as claimed in claim 17, wherein in a modeof operation said ultrasonic transducer remains essentially static andsaid microtitre or multi-well sample plate is translated relative tosaid ultrasonic transducer.
 19. An ion source as claimed in anypreceding claim, further comprising a device arranged and adapted toposition said ultrasonic transducer adjacent a sample well of amicrotitre or multi-well sample plate.
 20. An ion source as claimed inclaim 19, wherein in a mode of operation said microtitre or multi-wellsample plate remains essentially static and said ultrasonic transduceris translated relative to said microtitre or multi-well sample plate.21. An ion source as claimed in any of claims 17-20, wherein said samplefluid is contained, in use, within said sample well of said microtitreor multi-well sample plate.
 22. An ion source as claimed in any ofclaims 17-21, wherein said ultrasonic transducer is arranged to makefluid contact with said microtitre or multi-well sample plate.
 23. Anion source as claimed in any of claims 17-22, wherein in a mode ofoperation one or more droplets are sequentially ejected from differentsample wells of said microtitre or multi-well sample plate.
 24. An ionsource as claimed in any preceding claim, wherein said ultrasonictransducer is arranged and adapted to detect and/or measure reflectedultrasonic energy.
 25. An ion source as claimed in any preceding claim,further comprising a control system which is arranged and adapted todetermine one or more first properties of said sample fluid.
 26. An ionsource as claimed in claim 25, wherein said control system is arrangedand adapted to determine the surface height and/or surface positionand/or density of said sample fluid.
 27. An ion source as claimed inclaim 25 or 26, wherein said control system is arranged and adapted todetermine one or more first properties of said sample fluid using sonar.28. An ion source as claimed in claim 25, 26 or 27, wherein said controlsystem is arranged and adapted to determine one or more first propertiesof said sample fluid by determining the time of flight and intensity orenergy of a reflected sonar pulse.
 29. An ion source as claimed in claim28, wherein said sonar pulse has an energy in the range<100 mW, 100-200mW, 200-300 mW, 300-400 mW or 400-500 mW and/or has a relative lowenergy so as not to cause ejection of droplets from said sample fluid.30. An ion source as claimed in claim 29, wherein said sonar pulsereflects, in use, from a surface of said sample fluid.
 31. An ion sourceas claimed in any of claims 26-30, wherein said control system isarranged and adapted to control the focusing of said ultrasonic energyonto said surface of said sample fluid based upon said determined one ormore first properties of said sample fluid.
 32. An ion source as claimedin any preceding claim, wherein said ultrasonic transducer is arrangedto emit ultrasonic waves having a frequency in the range: (i) 20-30 kHz;(ii) 30-40 kHz; (iii) 40-50 kHz; (iv) 50-60 kHz; (v) 60-70 kHz; (vi)70-80 kHz; (vii) 80-90 kHz; (viii) 90-100 kHz; and (ix) >100 kHz.
 33. Amass spectrometer comprising an ion source as claimed in any precedingclaim.
 34. A mass spectrometer as claimed in claim 33, wherein said massspectrometer comprises an ion inlet.
 35. A mass spectrometer as claimedin claim 34, wherein said ion inlet leads from a substantiallyatmospheric pressure region to a substantially sub-atmospheric pressureregion.
 36. A mass spectrometer as claimed in claim 34 or 35, whereinsaid ultrasonic transducer is arranged and adapted to eject one or moredroplets adjacent said ion inlet so that resulting analyte moleculesand/or ions enter said mass spectrometer via said ion inlet.
 37. A massspectrometer as claimed in any of claims 33-36, further comprising a gasphase ion mobility spectrometer or separator, wherein said ion mobilityspectrometer or separator is arranged and adapted to separate analyteions temporally according to their ion mobility.
 38. A method ofionising a sample comprising: focusing ultrasonic energy onto a surfaceof a sample fluid without directly contacting said sample fluid.
 39. Amethod as claimed in claim 38, further comprising ionising dropletsejected from said sample fluid using an Atmospheric Pressure Ionisation(“API”) device.
 40. A method of mass spectrometry comprising a method ofionising a sample as claimed in claim 38 or
 39. 41. An ion source for amass spectrometer comprising: an ultrasonic transducer arranged andadapted to focus ultrasonic energy onto a surface of a sample fluidcontained, in use, within a sample well without said ultrasonictransducer directly contacting said sample fluid so as to eject one ormore droplets from said sample fluid in a controlled manner withoutforming an uncontrolled mist of droplets; and an ionisation devicearranged and adapted to ionise said one or more droplets.
 42. A methodof ionising a sample comprising: providing an ultrasonic transducer andfocusing ultrasonic energy onto a surface of a sample fluid containedwithin a sample well without said ultrasonic transducer directlycontacting said sample fluid so as to eject one or more droplets fromsaid sample fluid in a controlled manner without forming an uncontrolledmist of droplets; and ionising said one or more droplets.